Alcoholics are very frequently heavy users of tobacco products. In general, as the consumption of ethanol increases, so does tobacco use. During the last few years we have demonstrated that mice that have been selectively bred for differential sensitivity to ethanol, as measured by duration of ethanol-induced sleep-time, also differ in sensitivity to several of the behavioral and physiological effects elicited by a challenge dose of nicotine. These mice, the LS and SS mice, also differ in the development of tachyphylaxis, or behavioral desensitization, to nicotine and they differ in the effects of ethanol on this process. In all cases, the LS are more responsive. Similarly, the LS develop tolerance to nicotine and cross tolerance to ethanol whereas the SS do not, or do so less readily. The proposed studies will further explore the genetic regulation of ethanol and nicotine acute sensitivity, behavioral desensitization and tolerance and cross-tolerance development using the recombinant inbred starins (RI) that have been developed from the LS-SS mice. Rat strains that are being selectively bred for differential sleep-time will also be studied. Biochemical explanations for ethanol-nicotine interactions will be sought. Specifically, brain nicotinic receptors will be measured using autoradiograhpy; the kinetics of desensitization will be studied using in vitro binding methods, and the effects of ethanol on (14C)-2-deoxyglucose uptake will be measured. These studies should prove to be of value in understanding ethanol/nicotine interactions at brain nicotinic receptors as well as identifying brain regions that are affected similarly by these two drugs. The data obtained should prove useful in understanding the interactions between the two substances that are most frequently used by man.